Septic patients without obvious signs of infection at baseline are more likely to die in the ICU.

OBJECTIVE: Early identification of sepsis is mandatory. However, clinical presentation is sometimes misleading given the lack of infection signs. The objective of the study was to evaluate the impact on the 28-day mortality of the so-called "vague" presentation of sepsis. DESIGN: Single centre retrospective observational study. SETTING: One teaching hospital Intensive Care Unit. SUBJECTS: All the patients who presented at the Emergency Department (ED) and were thereafter admitted to the Intensive Care Unit (ICU) with a final diagnosis of sepsis were included in this retrospective observational three-year study. They were classified as having exhibited either "vague" or explicit presentation at the ED according to previously suggested criteria. Baseline characteristics, infection main features and sepsis management were compared. The impact of a vague presentation on 28-day mortality was then evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 348 included patients, 103 (29.6%) had a vague sepsis presentation. Underlying chronic diseases were more likely in those patients [e.g., peripheral arterial occlusive disease: adjusted odd ratio (aOR) = 2.01, (1.08-3.77) 95% confidence interval (CI); p = 0.028], but organ failure was less likely at the ED [SOFA score value: 4.7 (3.2) vs. 5.2 (3.1), p = 0.09]. In contrast, 28-day mortality was higher in the vague presentation group (40.8% vs. 26.9%, p = 0.011), along with longer time-to-diagnosis [18 (31) vs. 4 (11) h, p < 0.001], time-to-antibiotics [20 (32) vs. 7 (12) h, p < 0.001] and time to ICU admission [71 (159) vs. 24 (69) h, p < 0.001]. Whatever, such a vague presentation independently predicted 28-day mortality [aOR = 2.14 (1.24-3.68) 95% CI; p = 0.006]. CONCLUSIONS: Almost one third of septic patient requiring ICU had a vague presentation at the ED. Despite an apparent lower level of severity when initially assessed, those patients had an increased risk of mortality that could not be fully explained by delayed diagnosis and management of sepsis.

Time-to-antibiotics and clinical outcomes in patients with sepsis and septic shock: a prospective nationwide multicenter cohort study.

BACKGROUND: Timely administration of antibiotics is one of the most important interventions in reducing mortality in sepsis. However, administering antibiotics within a strict time threshold in all patients suspected with sepsis will require huge amount of effort and resources and may increase the risk of unintentional exposure to broad-spectrum antibiotics in patients without infection with its consequences. Thus, controversy still exists on whether clinicians should target different time-to-antibiotics thresholds for patients with sepsis versus septic shock. METHODS: This study analyzed prospectively collected data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Adjusted odds ratios (ORs) were compared for in-hospital mortality of patients who had received antibiotics within 1 h to that of those who did not. Spline regression models were used to assess the association of time-to-antibiotics as continuous variables and increasing risk of in-hospital mortality. The differences in the association between time-to-antibiotics and in-hospital mortality were assessed according to the presence of septic shock. RESULTS: Overall, 3035 patients were included in the analysis. Among them, 601 (19.8%) presented with septic shock, and 774 (25.5%) died. The adjusted OR for in-hospital mortality of patients whose time-to-antibiotics was within 1 h was 0.78 (95% confidence interval [CI] 0.61-0.99; p = 0.046). The adjusted OR for in-hospital mortality was 0.66 (95% CI 0.44-0.99; p = 0.049) and statistically significant in patients with septic shock, whereas it was 0.85 (95% CI 0.64-1.15; p = 0.300) in patients with sepsis but without shock. Among patients who received antibiotics within 3 h, those with septic shock showed 35% (p = 0.042) increased risk of mortality for every 1-h delay in antibiotics, but no such trend was observed in patients without shock. CONCLUSION: Timely administration of antibiotics improved outcomes in patients with septic shock; however, the association between early antibiotic administration and outcome was not as clear in patients with sepsis without shock.

Time to antibiotic administration in children with febrile neutropenia: Report from a low middle-income country.

Background & objectives: Antibiotic administration within one hour of presentation is a standard of care goal in the treatment of febrile neutropenia (FN). The objective of this study was to find the proportion of children with FN who had a time to antibiotic administration (TTA) of ≤60 min and evaluate causes for delay. Methods: A prospective analysis of children presenting with FN was carried out. The primary outcome was the proportion of patients who received antibiotics within one hour of triage. Predictor variables included the place of presentation, time and day of the week. A root cause analysis was done for delayed TTA. Results: A total of 211 children (mean age: 6 yr) with FN were evaluated for TTA. The primary outcome of TTA, (≤60 min) was achieved in 66 per cent children. The odds of delayed TTA were lower when patients were evaluated in the night. Odds of delayed TTA were higher in patients who had no focus of infection, when assessed in the oncology daycare and when assessed over the weekend, but none were statistically significant. Waiting for blood results (30%), delay in preparing antibiotics (21%) and delay in allotting bed (30%) were significant causes for delay. Interpretation & conclusions: Two-thirds of the patients achieved the target TTA of ≤60 min. Patients seen during the daytime and on weekends had a delay in TTA compared to those presenting at the evening or night or weekdays. Children with a focus for fever received antibiotics earlier. Logistics for admission and awaiting blood counts were chief causes for delay.

A Critical Analysis of the Literature on Time-to-Antibiotics in Suspected Sepsis.

The Surviving Sepsis Campaign recommends immediate antibiotics for all patients with suspected sepsis and septic shock, ideally within 1 hour of recognition. Immediate antibiotic treatment is lifesaving for some patients, but a substantial fraction of patients initially diagnosed with sepsis have noninfectious conditions. Aggressive time-to-antibiotic targets risk promoting antibiotic overuse and antibiotic-associated harms for this subset of the population. An accurate understanding of the precise relationship between time-to-antibiotics and mortality for patients with possible sepsis is therefore critical to finding the best balance between assuring immediate antibiotics for those patients who truly need them versus allowing clinicians some time for rapid investigation to minimize the risk of overtreatment and antibiotic-associated harms for patients who are not infected. More than 30 papers have been published assessing the relationship between time-to-antibiotics and outcomes, almost all of which are observational cohort studies. Most report significant associations but all have important limitations. Key limitations include focusing just on the sickest subset of patients (only patients requiring intensive care and/or patients with septic shock), blending together mortality estimates from patients with very long intervals until antibiotics with patients with shorter intervals and reporting a single blended (and thus inflated) estimate for the average increase in mortality associated with each hour until antibiotics, and failure to control for large potential confounders including patients' presenting signs and symptoms and granular measures of comorbidities and severity of illness. In this study, we elaborate on these potential sources of bias and try to distill a better understanding of what the true relationship between time-to-antibiotics and mortality may be for patients with suspected sepsis or septic shock.

Interventions aiming to reduce time to antibiotics (TTA) in patients with fever and neutropenia during chemotherapy for cancer (FN), a systematic review.

PURPOSE: Multiple interventions have been developed aiming to reduce time to antibiotics (TTA) in patients with fever and neutropenia (FN) following chemotherapy for cancer. We evaluated their effect to reduce TTA and their impact on important clinical outcomes in a systematic review. METHODS: The search covered seven databases. Biases and quality of studies were assessed with the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Interventions could be implemented in any setting and performed by any person included in the FN management. Absolute change of TTA was the primary outcome. Registration: PROSPERO (CRD42018092948). RESULTS: Six thousand two hundred ninety-six titles and abstracts were screened, 177 studies were retrieved and 30 studies were included. Risk of bias was moderate to serious in 28 studies and low in two studies. All but one study reported a reduction of TTA after the intervention. Various types of interventions were implemented; they most commonly aimed at professionals. Most of the studies made more than one single intervention. CONCLUSION: This review may help centers to identify their specific sources of delay and barriers to change and to define what intervention may be the best to apply. This review supports the assertion that TTA can be considered a measure of quality of care, emphasizes the importance of education and training, and describes the very different interventions which have effectively reduced TTA.

Association of time to antibiotics and clinical outcomes in patients with fever and neutropenia during chemotherapy for cancer: a systematic review.

PURPOSE: Prompt antibiotic therapy is standard of care for patients with fever and neutropenia (FN) during chemotherapy for cancer. We systematically reviewed the association between time to antibiotics (TTA) and clinical outcomes. METHODS: The search covered seven databases; confounding biases and study quality were assessed with the ROBINS-I tool. Safety (death, intensive care unit (ICU) admission, sepsis) and treatment adequacy (relapse of infection, persistence or recurrence of fever) were assessed as primary outcomes. RESULTS: Of 6296 articles identified, 13 observational studies were included. Findings regarding safety were inconsistent. Three studies controlling for triage bias showed a possible association between longer TTA and impaired safety. Meta-analysis for TTA ≤ 60 min versus > 60 min was feasible on four studies, with three studies each reporting on death (OR 0.78, 95%CI 0.16-3.69) and on ICU admission (OR 1.43, 95%CI 0.57-3.60). No study reported data on treatment adequacy. Triage bias, i.e. faster treatment of patients with worse clinical condition, was identified as a relevant confounding factor. CONCLUSION: There seems to be an association between longer TTA and impaired safety. More knowledge about TTA effects on safety are important to optimise treatment guidelines for FN. Controlling for triage and other biases is necessary to gain further evidence. TRIAL REGISTRATION: Registration: PROSPERO [http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018092948].

Utilization of a multidisciplinary emergency department sepsis huddle to reduce time to antibiotics and improve SEP-1 compliance.

Sepsis is a significant public health crisis in the United States, contributing to 50% of inpatient hospital deaths. Given its dramatic health effects and implications in the setting of new CMS care guidelines, ED leaders have renewed focus on appropriate and timely sepsis care, including timely administration of antibiotics in patients at risk for sepsis. Modeling the success of multidisciplinary bedside huddles in improving compliance with appropriate care in other healthcare settings, a Sepsis Huddle was implemented in a large, academic ED, with the goal of driving compliance with standardized sepsis care as described in the CMS SEP-1 measure. A retrospective cohort analysis was performed, with the primary finding that utilization of the Sepsis Huddle resulted in antibiotics being administered on average 41 min sooner than when the Sepsis Huddle was not performed. Given that literature suggests that early administration of appropriate antibiotic therapy is a major driver of mortality reduction in patients with sepsis, this study represents a proof of concept that utilization of a Sepsis Huddle may serve to improve outcomes among ED patients at risk for sepsis.

A nurse-led protocol improves the time to first dose intravenous antibiotics in septic patients post chemotherapy.

PURPOSE: Neutropenic sepsis is a time-dependent emergency with early interventions shown to improve outcomes. Broad spectrum intravenous antibiotic administration is the initial therapy in patients with suspected neutropenic sepsis. Compliance with early antibiotic administration in febrile neutropenia patients is poor. Innovations have been trialled to improve the time to first dose intravenous antibiotics in patients with suspected neutropenic sepsis. Consideration of extending first dose intravenous antibiotic prescribing to trained nursing staff may improve performance in this key standard. METHODS: A retrospective analysis was performed at a specialist oncology hospital in the North West of England from January 1st 2015 to January 31st 2016. The nurses on the Medical Admissions Unit (MAU) have been given the responsibility of assessing patients presenting with fever post chemotherapy including prescribing and administering the first dose of intravenous antibiotics with the aim of improving the speed of this intervention. RESULTS: During the study period, 697 patients presented to the MAU with suspected sepsis post chemotherapy. Six hundred seventy-two (96.4 %) patients received their first dose of intravenous antibiotics within 60 min of presentation to the MAU. Of this group, 323 (48.1 %) were administered antibiotics within 15 min of arrival. Of the 25 (3.6 %) patients who did not receive antibiotics within 1 h, root cause analysis revealed the reason in 23 (92 %) patients was an inability to ascertain intravenous access. CONCLUSION: Nurse-led protocols are an effective, safe, and sustainable method for achieving early antibiotic administration in patients with suspected febrile neutropenia. This is a key component of ensuring improved outcomes for this cohort of patients.

Identifying high-risk phenotypes and associated harms of delayed time-to-antibiotics in patients with ICU onset sepsis: A retrospective cohort study.

PURPOSE: To identify phenotypes of Intensive Care Unit (ICU) onset sepsis and its associated harms of delayed time-to-antibiotics. MATERIALS AND METHODS: The Medical Information Mart for Intensive Care IV (MIMIC-IV) database was employed to identify patients with ICU onset sepsis. The primary exposure was time-to-antibiotics, as measured from sepsis recognition to first antibiotic administered. Latent profile analysis (LPA) was used to identify phenotypes of sepsis based on individual organ failure score derived from Sequential Organ Failure Assessment (SOFA). Interactions between phenotypes and time-to-antibiotics on 28-day mortality were explored. RESULTS: 6246 patients were enrolled in final analysis. The overall 28-day mortality was 12.7%. Delayed time-to-antibiotics was associated with increased 28-day mortality in patients with ICU onset sepsis (HR 1.12, 95% CI 1.08-1.18). Four phenotypes of sepsis were identified: phenotype 1 was characterized by respiratory dysfunction, phenotype 2 was characterized by cardiovascular dysfunction, phenotype 3 was characterized by multiple organ dysfunction, and phenotype 4 was characterized by neurological dysfunction. The adjusted HR of 28-day mortality was 1.16 (95% CI 1.08-1.25) in phenotype 1, and 1.06 (95% CI 1.00-1.13) in phenotype 2, while no significant interaction was observed. CONCLUSIONS: Septic patients with respiratory or cardiovascular dysfunction were associated with harms of delayed time-to-antibiotics.

Late-Onset Sepsis Mortality among Preterm Infants: Beyond Time to First Antibiotics.

Objective: To investigate the impact of timing, in vitro activity and appropriateness of empirical antimicrobials on the outcome of late-onset sepsis among preterm very low birth weight infants that are at high risk of developing meningitis. Study design: This retrospective study included 83 LOS episodes in 73 very low birth weight infants born at ≤32 weeks' gestation with positive blood and/or cerebrospinal fluid culture or polymerase chain reaction at >72 h of age. To define the appropriateness of empirical antimicrobials we considered both their in vitro activity and their ideal delivery through the blood-brain barrier when meningitis was confirmed or not ruled out through a lumbar puncture. The primary outcome was sepsis-related mortality. The secondary outcome was the development of brain lesions. Timing, in vitro activity and appropriateness of empirical antimicrobials, were compared between fatal and non-fatal episodes. Uni- and multi-variable analyses were carried out for the primary outcome. Results: Time to antibiotics and in vitro activity of empirical antimicrobials were similar between fatal and non-fatal cases. By contrast, empirical antimicrobials were appropriate in a lower proportion of fatal episodes of late-onset sepsis (4/17, 24%) compared to non-fatal episodes (39/66, 59%). After adjusting for Gram-negative vs. Gram-positive pathogen and for other supportive measures (time to volume administration), inappropriate empirical antimicrobials remained associated with mortality (aOR, 10.3; 95% CI, 1.4-76.8, p = 0.023), while timing to first antibiotics was not (aOR 0.9; 95% CI, 0.7-1.2, p = 0.408; AUC = 0.88). The association between appropriate antimicrobials and brain sequelae was also significant (p = 0.024). Conclusions: The risk of sepsis-related mortality and brain sequelae in preterm very low birth weight infants is significantly associated with the appropriateness (rather than the timing and the in vitro activity) of empirical antimicrobials. Until meningitis is ruled out through lumbar puncture, septic very low birth weight infants at high risk of mortality should receive empiric antimicrobials with high delivery through the blood-brain barrier.

Timing and Spectrum of Antibiotic Treatment for Suspected Sepsis and Septic Shock: Why so Controversial?

Sepsis guidelines and mandates encourage increasingly aggressive time-to-antibiotic targets for broad-spectrum antimicrobials for suspected sepsis and septic shock. This has caused considerable controversy due to weaknesses in the underlying evidence and fear that overly strict antibiotic deadlines may harm patients by perpetuating or escalating overtreatment. Indeed, a third or more of patients currently treated for sepsis and septic shock have noninfectious or nonbacterial conditions. These patients risk all the potential harms of antibiotics without their possible benefits. Updated Surviving Sepsis Campaign guidelines now emphasize the importance of tailoring antibiotics to each patient's likelihood of infection, risk for drug-resistant pathogens, and severity-of-illness.

The impact of emergency antibiotic administration time on patients with sepsis.

OBJECTIVES: To assess the mortality benefits of timely antibiotic treatment of adults present at the emergency department with sepsis and compare one-hour administration and 3-hour administration starting from the time of triage. METHODS: In this retrospective study, we used secondary data analysis to investigate the utility of the National Early Warning Score as a predictor of mortality in sepsis patients between July 2018 and June 2019, at the Emergency Department, King Saud Medical City, Riyadh, Saudi Arabia. The patients were grouped into 2 based on the time interval from triage to the first antibiotic administration: the immediate group received antibiotics within the first hour, and the early group received antibiotics between one and 3 hours. The primary outcome of interest was in-hospital mortality. RESULTS: Out of 495 septic patients, only 292 patients (mean age of 56.3 ± 23.6 years) met the inclusion criteria. Two hundred fifty (85.6%) patients received antibiotics within one hour of triage (immediate), while 42 (14.4%) patients received antibiotics between one and 3 hours (early). Overall, in-hospital mortality was 31.8%. The mortality rates among patients who received early antibiotic was 31.6% and who received immediate antibiotic was 33.3%, with a p-value of 0.823. CONCLUSION: Our findings did not support immediate antibiotic administration over early administration in patients with sepsis. However, further studies are recommended to investigate the effects of antibiotic timing on the outcome of severe sepsis patients.

The importance of a hospital-dedicated sepsis response team.

INTRODUCTION: As sepsis is a life-threatening disease, appropriate measures should be started as soon as possible after diagnosis. Duration until first therapy affects survival. However, guideline adherence of primary sepsis care is often low. Dedicated sepsis response teams (SRT) may improve primary sepsis care. AREAS COVERED: PubMed was searched for studies investigating the effect of an implementation of SRTs. This review discusses the results of five studies presenting results before and after implementation of SRTs. The importance of choosing the alert and the right team composition of the SRT is also discussed. EXPERT OPINION: Implementing SRTs is associated with a better compliance with guidelines regarding primary sepsis care and with a reduction in hospital mortality. However, scientific evidence of the studies is limited due to chosen study design. SRTs can be a strong method to improve primary sepsis care in specific hospital settings if the pros and cons against the other measures of quality improvement are considered and the technical details such as alerts and team members are customized to the individual hospital setting.

Protocol for a systematic review of time to antibiotics (TTA) in patients with fever and neutropenia during chemotherapy for cancer (FN) and interventions aiming to reduce TTA.

BACKGROUND: Fever and neutropenia (FN) is a common complication of chemotherapy for cancer. Prompt empiric broad-spectrum antibiotic therapy in FN is typically considered standard of care, but the definition of prompt is not clear. We seek to systematically review the available data on the association between time to antibiotics (TTA) administration and clinical outcomes in patients with FN being treated with chemotherapy. There have been several efforts to reduce TTA in patients with FN, by implementing specific interventions, presuming there will be a beneficial effect on patient-important outcomes. This systematic review will also collect data on such interventions and their effect to reduce TTA and potentially change clinical outcomes. METHODS/DESIGN: The search will cover MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, CDSR, CENTRAL, and LILACS. A full-search strategy is provided. Lists of studies identified by references cited and forward citation searching of included articles will also be reviewed. Studies will be screened, and data extracted by one researcher and independently checked by a second. Confounding biases and quality of studies will be assessed with the risk of bias in non-randomised studies-of interventions (ROBINS-I) tool. Data will be presented in narrative and tabular forms; in addition, if appropriate data is available, random effects meta-analysis will be used to examine TTA. A detailed analysis plan, including an assessment of heterogeneity and publication bias, is provided. DISCUSSION: This study aims to evaluate the association between TTA and patient-important clinical outcomes. Additionally, it will identify, critically appraise, and synthesise information on performed interventions and its effect to reduce TTA as a way of gaining insight into the potential use of these approaches. This will provide better knowledge for an adjusted treatment approach of FN. SYSTEMATIC REVIEW REGISTRATION: PROSPERO [ CRD42018092948 ].

Time to antibiotics administration and outcome in community-acquired pneumonia: Secondary analysis of a randomized controlled trial.

BACKGROUND: The association between early antibiotic administration and outcomes remains controversial in patients hospitalized for community-acquired pneumonia. METHODS: We performed a secondary analysis of a randomized controlled trial comparing two antibiotic treatment strategies for patients hospitalized for moderately severe CAP. The univariate and multivariate associations between time to antibiotic administration (TTA) and time to clinical stability were assessed using a Cox proportional hazard model. Secondary outcomes were death, intensive care unit admission and hospital readmission up to 90days. RESULTS: 371 patients (mean age 76years, CURB-65 score≥2 in 52%) were included. Mean TTA was 4.35h (SD 3.48), with 58.5% of patients receiving the first antibiotic dose within 4h. In multivariate analysis, number of symptoms and signs (HR 0.876, 95% CI 0.784-0.979, p=0.020), age (HR 0.986, 95% CI 0.975-0.996, p=0.007), initial heart rate (HR 0.992, 95% CI 0.986-0.999, p=0.023), and platelets count (HR 0.998, 95% CI 0.996-0.999, p=0.004) were associated with a reduced probability of reaching clinical stability. The association between TTA and time to clinical stability was not significant (HR 1.009, 95% CI 0.977-1.042, p=0.574). We found no association between TTA and the risk of intensive care unit admission, death or readmission up to 90days after the initial admission. CONCLUSION: In patients hospitalized for moderately severe CAP, a shorter time to antibiotic administration was not associated with a favorable outcome. These findings support the current recommendations that do not assign a specific time frame for antibiotics administration.

Sepsis Alert - a triage model that reduces time to antibiotics and length of hospital stay.

OBJECTIVE: To study if a modified triage system at an Emergency Department (ED) combined with educational efforts resulted in reduced time to antibiotics and decreased length of hospital stay (LOS) for patients with severe infection. METHODS: A retrospective, observational study comparing patients before and after the start of a new triage model at the ED of a University Hospital. After the implementation of the model, patients with fever and abnormal vital signs were triaged into a designated sepsis line (Sepsis Alert) for rapid evaluation by the attending physician supported by a infectious diseases (IDs) specialist. Also, all ED staff participated in a designated sepsis education before Sepsis Alert was introduced. Medical records were evaluated for patients during a 3-month period after the triage system was started in 2012, and also during the corresponding months in 2010 and 2014. RESULTS: A total of 1837 patients presented with abnormal vital signs. Of these, 221 patients presented with fever and thus at risk of having severe sepsis. Among patients triaged according to the new model, median time to antibiotics was 58.5 at startup and 24.5 minutes at follow-up two years later. This was significantly less than for patients treated before the new model, 190 minutes. Also, median LOS was significantly decreased after introduction of the new triage model, from nine to seven days. CONCLUSIONS: A triage model at the ED with special attention to severe sepsis patients, led to sustained improvements of time to antibiotic treatment and LOS.